Project Summary/Abstract Methamphetamine (MA) dependence is prevalent in many regions of the United States. Important sequelae of this illness include cognitive impairment, hepatitis B and C, and HIV infection. Cognitive impairment and withdrawal symptoms, e.g., somnolence, fatigue, and craving, may put users at risk for relapse. There is no established pharmacotherapy for MA dependence. Modafinil is a novel wake-promoting agent that relieves fatigue, enhances cognitive function, is well tolerated, and has low abuse liability. Modafinil blunts the subjective effects of cocaine, reduces cocaine use in outpatients, and recently completed work by our group indicates that it is safe when co-administered with intravenous MA. An 8-week dose ranging study will be conducted to assess the effect size of modafinil for treatment of MA dependence. MA dependent subjects will be randomly assigned to receive either 200 or 400 mg per day of modafinil or placebo. Assessments will include urinalysis for MA, self-report of MA use, the Addiction Severity Index, the Risk for AIDS Behaviors, a neurocognitive test battery, the Amphetamine Withdrawal Questionnaire, plasma modafinil levels, blood chemistries, and adverse event reports. A generalized estimating equation model of a composite measure of self-report and urine toxicology be used to assess the effect of modafinil dose on MA use. Pharmacokinetic/pharmacodynamic (PK/PD) modeling will used to determine the relationship between modafinil plasma concentration and outcomes. We hypothesize that 1) modafinil will be safe and well tolerated, 2) persons given 400 mg modafinil will use less MA than those given placebo, and 3) PK/PD modeling will reveal concentration-effect relationships between modafinil levels and a) cognitive function, b) withdrawal symptoms, and c) MA use. Project Narrative Methamphetamine addiction is a serious problem in the United States for which no medications have been shown to be helpful. Modafinil is a medication that is used to treat sleep disorders, has shown promise as a cocaine addiction treatment, and may help the withdrawal and difficulty thinking that methamphetamine users have when quitting. We will conduct a randomized trial of placebo (sugar pill) and two doses of modafinil to see which dose is most useful in treating methamphetamine-addicted outpatients.